Osteonecrosis is a distinct clinical and pathological entity, with many different causes and differing pathogeneses. Although much has been written about the disorder, all the factors in the aetiology and pathogenesis are not known at this time. Osteonecrosis can affect an area spontaneously in adults and children (Perthes disease), or result from such disease processes as alcoholism, exposure to glucocorticoids and or cytotoxic drugs, exposure to a hyperbaric environment (caisson disease)i, fracture, infection, haematological disease, to name some examples. No proven pharmacological agent is currently available for the treatment of osteonecrosis.
The consequences of this disorder are severe as osteonecrosis usually affects the function of a joint and most commonly the hip joint. If the hip joint is affected, the femoral head is susceptible to collapse, leading to pain, stiffness and long-term disability. The affected joint is further susceptible to deformity and osteoarthritis. Osteonecrosis having unknown aetiology affects a significant percentage of the population including children. Particularly, Perthes disease (Legg-Calve-Perthes disease) is common, with an incidence of 8.5 to 21 per 100,000 children per annumii,iii,iv,v. The aetiology of Perthes disease remains unknown, but the common final pathway of the majority of theories suggest a vascular insult resulting in a period of relative ischaemia and osteonecrosis, leading to resorption and collapse of the necrotic epiphysis.vi,vii,viii.
Perthes disease is well known to lead to osteoarthritis. By age 56, 40% of affected patients in one study underwent total hip replacement surgery. Subchondral bony collapse proceeds as the femoral head becomes weaker and more osteoporotic. There is currently no known effective medical treatment for Perthes disease. Mechanical treatments such as bracing have been largely discarded, as they have not proven to alter the natural history of the disorderix,x. Current opinion dictates that if a child's hip reaches a certain degree of deformity, an operation is indicated to place the femoral head in a better position in the joint in an attempt to produce a more spherical hip, and thus better long term outcome. Few of the surgical options are designed to prevent collapse and are aimed at salvaging the situation once collapse and deformity of the hip have ensued. Current surgical therapies meet with limited or mixed successxi,xii,xiii.
There are other situations where osteonecrosis of the femoral head is also manifest in childhood. Children with malignant disease are particularly prone to developing osteonecrosis. Mattano et al showed that of 1,409 children with acute lymphoblastic leukaemia (ALL) the 3-year life-table incidence of developing osteonecrosis is 9.3%xiv. In that study symptoms of pain and/or immobility were chronic in 84% of patients, with 24% having undergone an orthopaedic procedure and an additional 15% considered candidates for surgery in the future. In a prospective MRI study of 24 children with acute lymphoblastic leukaemia, Ojala et al documented osteonecrosis in 38%xv.
Osteonecrosis also occurs in patients who are recovering from bone marrow, kidney, lung and liver transplantationxvi,xvii,xviii,xix. Children who sustain a fracture of the neck of the femur can also go on to suffer from osteonecrosis of the femoral head, as can children with slipped upper femoral epiphysis. The outcome in patients is often poor if they develop avascular necrosisxx. In a recent study of femoral neck fracture in children, avascular necrosis occurred in 40%xxi.
In adult patients, progressive collapse of the bone and cartilage of the joint ensues, often coinciding with a subchondral fracture. In a prospective study of osteonecrosis of the femoral head, Ito et al found that 64% were symptomatic at mean six-year follow-upxxii. In older persons, progressive collapse and deformity of the femoral head can be rapid, with 66% of patients progressing to collapse within a short period, and 22% having rapid resorption and destruction of the femoral headxxiii. For these elderly patients, exposure to total hip arthroplasty surgery to resolve the subsequent pain and immobility of their hip poses considerable risk.
Surgical solutions for osteonecrosis include core decompression to reduce the intraosseous pressure and increase new blood supply; bone grafting, either through the core decompression or through the joint (trapdoor procedure); vascularised bone and/or tissue transplantation; and redirectional osteotomy of the affected segment away from load. Containment treatment in Perthes disease, either non-operative or operative, in an attempt to reshape the collapsed femoral head, is well described. The use of an external fixator or brace to unload the joint and prevent collapse of the affected part is also well described. Surgical treatment of the related disease osteochondritis dissecans usually involves stabilising a fragment of subchondral bone which has become detached from the adjacent bone with a fixation device, with or without bone grafting and drilling of the bone. Sometimes excision of the fragment is required.
Recent techniques involve the treatment of osteonecrosis with hyperbaric oxygen, however, some authors have theorised that caisson disease may be due to hyperbaric oxygen rather than nitrogenxxiv. Indeed, in a recent study of 20 children presenting with osteonecrosis in the course of cytotoxic chemotherapy, no difference was found in sequential MRI in the group treated with hyperbaric oxygen than in control subjectsxxv.
Despite the availability of such treatments, the prognosis for diseases such as osteonecrosis and osteochondritis dissecans is poor. Once the condition is identified, collapse of the affected bone continues over months to years, leading to deformity and osteoarthritis of the relevant joint.
Both conditions can lead to immobility of the patient and the cost to the individual and community is great particularly as osteonecrosis and particularly osteochondritis dissecans often occur in young, healthy patients.
Total joint replacement, often at a young age—with its attendant complications and short life span, is often required to resolve the pain and suffering of such individuals. A pharmacological therapy, therefore, offers these patients enormous benefits.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.